Gadd45 proteins are key players in cellular stress responses. These proteins interact with cell cycle &stress response proteins, including PCNA, p21, Cdc2/cyclinB1, MEKK4 &p38 kinase. Taking advantage of the gadd45 null mice several important observations have been made. This includes evidence that gadd45 genes play an important role in regulating the response of hematopoietic cells to genotoxic &physiological stress, including acute stimulation by hematopoietic cytokines, myeloablating agents &inflammatory substances. The unifying hypothesis is that Gadd45 proteins are modulators of interrelated hematopoietic stress signaling pathways in response to genotoxic &physiological stimuli, and have distinct roles in sub-compartments of the hematopoietic cascade;in addition, Gadd45 functions are manifested by binding to partner proteins implicated in stress signaling. Gadd45a and Gadd45b play pro-survival roles, protecting myeloid cells from genotoxic stress induced cell death, including ultraviolet-radiation (UV), VP-16 &daunorubicin (DNR). Aim 1 is targeted at elucidating signaling pathways via which Gadd45 proteins protect myeloid cells from genotoxic stress. Evidence was obtained that Gadd45a &Gadd45b modulate survival &differentiation of myeloid progenitors in response to acute stimulation with differentiating cytokines. Experiments proposed in Aim 2 are targeted at assessing how Gadd45 proteins interact with partners to regulate the program of terminal differentiation following acute stimulation with differentiating cytokines, conditions that mimic what occurs during inflammatory stress. Preliminary evidence shows that Gadd45b and Gadd45a also modulate the function of hematopoietic stem cells (HSC). Aim 3 will determine what role(s) these Gadd45 proteins play in modulating HSC functions. This research plan should result in increased understanding of stress responses of hematopoietic cells, &set the stage to evaluate, in clinically relevant settings, the impact the status of Gadd45 proteins has on the efficacy of chemotherapeutic agents &anti inflammatory drugs.